United States patent publication No. US20120295863 discloses dual-action compounds targeting adenosine A2A receptor and adenosine transporter for prevention and treatment of neurodegenerative diseases. A selective A2A adenosine receptor (A2AR) agonist named CGS21680 (in short, CGS) has been shown to be able to attenuate Huntington's disease (HD) symptoms in a transgenic mouse model, and rescue the urea cycle deficiency of HD disease by enhancing the activity of the ubiquitin-proteasome system (Chiang et al., 2009 Hum Mol Genet. 18:2929-2942; Chou et al., 2005 J Neurochem. 93:310-320). However, CGS is known to exert strong immunosuppressive effect and other side effects, and is therefore not suitable for clinical use.
N6-(4-hydroxybenzyl)adenosine, designated as T1-11 in US20120295863 and also an A2AR agonist, has been suggested to have a therapeutic potential in treating neural degenerative diseases. However, it is still difficult to develop T1-11 as an orally available drug due to its poor bioavailability (F<5%). Oral bioavailability is an important property in drug development because it represents the percentage of a substance that reaches systemic circulation after absorption and metabolism.